Thyroid autoimmunity and autoimmune thyroid disease in Malaysian girls with Turner syndrome: An understudied population.

AIMS: Knowledge on the spectrum of thyroid disorders amongst Turner syndrome (TS) patients in Southeast Asia is limited. This study aimed to evaluate the prevalence of thyroid autoimmunity, the spectrum of autoimmune thyroid disease and association with age and karyotype amongst Malaysian TS girls. METHODS: A cross-sectional study was conducted at 11 paediatric endocrine units in Malaysia. Blood samples for antithyroglobulin antibodies, antithyroid peroxidase antibodies and thyroid function test were obtained. In patients with pre-existing thyroid disease, information on clinical and biochemical thyroid status was obtained from medical records. RESULTS: Ninety-seven TS patients with a mean age of 13.4 ± 4.8 years were recruited. Thyroid autoimmunity was found in 43.8% of TS patients. Nineteen per cent of those with thyroid autoimmunity had autoimmune thyroid disease (Hashimoto thyroiditis in 7.3% and hyperthyroidism in 1% of total population). Patients with isochromosome X and patients with 45,X mosaicism or other X chromosomal abnormalities were more prone to have thyroid autoimmunity compared to those with 45,X karyotype (OR 5.09, 95% CI 1.54-16.88, P = 0.008 and OR 3.41, 95% CI 1.32-8.82, P = 0.01 respectively). The prevalence of thyroid autoimmunity increased with age (33.3% for age 0-9.9 years; 46.8% for age 10-19.9 years and 57.1% age for 20-29.9 years) with autoimmune thyroid disease detected in 14.3% during adulthood. CONCLUSION: Thyroid autoimmunity was significantly associated with the non 45,X karyotype group, particularly isochromosome X. Annual screening of thyroid function should be carried out upon diagnosis of TS until adulthood with more frequent monitoring recommended in the presence of thyroid autoimmunity.

SARS-CoV-2 viral RNA load dynamics in the nasopharynx of infected children.

It is important to understand the temporal trend of the paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined the differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. Serial cycle threshold values of SARS-CoV-2 from the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral loads (mean cycle threshold on day 7 of illness 28.6 vs. 36.7, P = 0.02). Peak SARS-CoV-2 viral loads occurred around day 2 of illness in infected children. Although we were unable to directly demonstrate infectivity, the detection of significant amount of virus in the upper airway of asymptomatic children suggest that they have the potential to shed and transmit SARS-CoV-2. Our study highlights the importance of contact tracing and screening for SARS-CoV-2 in children with epidemiological risk factors regardless of their symptom status, in order to improve containment of the virus in the community, including educational settings.

A patient with massive cerebral arterial air embolism.

Cerebral air embolism is potentially a catastrophic event that occurs as a consequence of air entry into the vasculature. We report a mechanically ventilated 72-year-old woman who underwent multiple procedures during intensive care stay with few possible sources of emboli postulated. We also discuss regarding the preventive measures to minimise the risk of air embolism.

SNX27 links DGKζ to the control of transcriptional and metabolic programs in T lymphocytes.

Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation and metabolic reprogramming. SNX27 limits the activation of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). SNX27 silencing in human T cells enhanced T cell receptor (TCR)-stimulated activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-mediated transcription. Transcription did not increase upon DGKζ silencing, suggesting that DGKζ function is dependent on SNX27. The enhanced transcriptional activation in SNX27-silenced cells contrasted with defective activation of the mammalian target of rapamycin (mTOR) pathway. The analysis of Snx27 -/- mice supported a role for SNX27 in the control of T cell growth. This study broadens our understanding of SNX27 as an integrator of lipid-based signals with the control of transcription and metabolic pathways.

Validity and reliability of the Moxy oxygen monitor during incremental cycling exercise.

INTRODUCTION: The Moxy is a novel, cutaneously placed muscle oxygen monitor which claims to measure local oxygen saturation (SmO2) and total haemoglobin (THb) using near-infrared spectroscopy. If shown to be reliable, its data storage and telemetric capability will be useful for assessing localised O2 usage during field-based exercise. This study investigated the reliability of the Moxy during cycling and assessed the correlations between its measurements, whole-body O2 consumption (VO2) and heart rate (HR). METHODS: Ten highly trained cyclists performed an incremental, step-wise cycling protocol on two occasions while wearing the Moxy. SmO2, THb, VO2 and HR were recorded in the final minute of each five-minute stage. Data were analysed using Spearman's Order-Rank Coefficient (SROC), Intraclass Correlation (ICC), and Coefficient of Variance (COV). Significance was set at p ≤ .05. RESULTS: SmO2 showed a 'strong' or 'very large' correlation between trials (SROC: r = 0.842-0.993, ICC: r = 0.773-0.992, p ≤ .01) and was moderately correlated with VO2 and HR (r = -0.71-0.73, p ≤ .01). SmO2 showed a moderate to high reliability at low intensities, but this decreased as relative exercise intensity increased. THb showed poor correlations between tests and with the other measured variables, but was highly reliable at all power outputs. CONCLUSIONS: The Moxy is a reliable device to measure SmO2 at low to moderate intensities, but at higher intensities, greater variation in measurements occurs, likely due to tissue ischaemia or increased movement artefacts due to more frequent muscular contractions. THb has low variation during exercise, and does not appear to be a valid indicator of muscle oxygenation.

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.

Quality of life in cadaver and living-related renal transplant recipients in Kuala Lumpur hospital.

OBJECTIVE: To examine the quality of life in cadaver (CAD) and living-related (LRRT) renal transplant recipients. METHODS: A cross-sectional study was done on patients followed in renal transplant clinic from 1/4/03 to 1/7/03 using the SF-36 questionnaire. Inclusion criteria were age >16 years,minimum of 3 months' posttransplant, and informed consent. Exclusion criteria were current treatment for rejection or infection or any life-threatening conditions. Information on duration of transplant, duration of dialysis prior to transplant, number of co-morbidities, and sociodemodraphic data were collected. RESULTS: Sixty-four among 110 patients (58.1%) completed the SF36 questionnaire. The LRRT recipients were younger, had a longer duration of transplant, and had spent significantly less time on dialysis prior to transplant compared to CAD transplant patients. Overall, the physical composite and the mental composite scores were not significantly different between the two transplant groups. Age was negatively associated with the physical composite score (Spearman's rho -0.251, P < .05) and bodily pain (Spearman's rho -0.266, P < .05). Duration of dialysis prior to transplant was negatively correlated with social functioning (Spearman's rho -0.28, P < .05) and mental health (Spearman's rho -0.39, P < .005). In multiple regression analysis, age was a significant predictor of the SF36 physical composite score (P < .05). CONCLUSION: This study shows that the quality of life between LRRT and CAD recipients was not significantly different. Increased age was associated with poorer physical capacity.

Stroke disease management--a framework for comprehensive stroke care.

Disease management is an approach to patient care that coordinates medical resources for the patient across the entire healthcare delivery system throughout the lifetime of the patient with the disease. Stroke is suitable for disease management as it is a well-known disease with a high prevalence, high cost, variable practice pattern, poor clinical outcome, and managed by a non-integrated healthcare system. It has measurable and actionable outcomes, with available local expertise and support of the Ministry of Health. Developing the programme requires a multidisciplinary team, baseline data on target populations and healthcare services, identification of core components, collaboration with key stakeholders, development of evidence-based clinical practice guidelines and carepaths, institution of care coordinators, use of information technology and continuous quality improvement to produce an effective plan. Core components include public education, risk factor screening and management, primary care and specialist clinics, acute stroke units, inpatient and outpatient rehabilitation facilities, and supportive community services including medical, nursing, therapy, home help and support groups for patients and carers. The family physician plays a key role. Coordination of services is best done by a network of hospital and community-based care managers, and is enhanced by a coordinating call centre. Continuous quality improvement is required, with audit of processes and outcomes, facilitated by a disease registry. Pitfalls include inappropriate exclusion of deserving patients, misuse, loss of physician and patient independence, over-estimation of benefits, and care fragmentation. Collaboration and cooperative among all parties will help ensure a successful and sustainable programme.

Cortical expression of endothelin receptor subtypes A and B following middle cerebral artery occlusion in rats.

This work aimed to define the spatial expression of endothelin A (ET(A)) and B (ET(B)) receptors in the cerebral cortex after permanent middle cerebral artery occlusion (MCAO) and to identify the phenotype of cells expressing ET(A) and ET(B) receptors. Cortical expression of ET(A) and ET(B) receptors was determined at the mRNA level by semi-quantitative reverse transcription-polymerase chain reaction and at the protein level by immunofluorescence staining, 12, 24 and 72 h after MCAO. Cells expressing endothelin receptors were phenotyped by double labelling with antibodies, anti-protein gene product (PGP9.5) and anti-ED1, towards neurons and activated microglia/macrophages, respectively. Both ET(A) and ET(B) receptor mRNA expressions increased significantly in the ipsilateral cortex in a time-dependent manner after MCAO. Robust expression of ET(A) receptors was noted in most neurons of the ischemic core and in several neurons in laminae 3 and 4 of the peri-infarct region 24 and 72 h after MCAO. ET(B) receptor immunoreactivity was observed in activated microglia/macrophages, beginning 24 h after MCAO. These results provide the first evidence that the action of endothelin during ischemia may be mediated by neuronal ET(A) receptors and activated microglia/macrophage ET(B) receptors. This differential localization of ET(A) and ET(B) receptors suggests that endothelin is involved in some complex neuron-glial interactions in addition to its vascular modulatory activity during ischemia.

Infection of central nervous system by motile Enterococcus: first case report.

A 66-year-old man with four indwelling ventriculoperitoneal shunts for multiloculated hydrocephalus from a complicated case of meningitis a year before developed shunt infection based on a syndrome of fever, drowsiness, and cerebrospinal fluid neutrophil pleocytosis in the background of repeated surgical manipulation to relieve successive shunt blockages. The cerebrospinal fluid culture, which yielded a motile Enterococcus species, was believed to originate from the gut. This isolate was lost in storage and could not be characterized further. The patient improved with vancomycin and high-dose ampicillin therapy. He relapsed a month later with Enterococcus gallinarum shunt infection, which responded to high-dose ampicillin and gentamicin therapy. This is probably the first case report of motile Enterococcus infection of the central nervous system.

Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex.

Gene-specific targeting of the Sin3 corepressor complex by DNA-bound repressors is an important mechanism of gene silencing in eukaryotes. The Sin3 corepressor specifically associates with a diverse group of transcriptional repressors, including members of the Mad family, that play crucial roles in development. The NMR structure of the complex formed by the PAH2 domain of mammalian Sin3A with the transrepression domain (SID) of human Mad1 reveals that both domains undergo mutual folding transitions upon complex formation generating an unusual left-handed four-helix bundle structure and an amphipathic alpha helix, respectively. The SID helix is wedged within a deep hydrophobic pocket defined by two PAH2 helices. Structure-function analyses of the Mad-Sin3 complex provide a basis for understanding the underlying mechanism(s) that lead to gene silencing.

Predicting non-elective hospital readmissions: a multi-site study. Department of Veterans Affairs Cooperative Study Group on Primary Care and Readmissions.

OBJECTIVE: To determine clinical and patient-centered factors predicting non-elective hospital readmissions. DESIGN: Secondary analysis from a randomized clinical trial. CLINICAL SETTING: Nine VA medical centers. PARTICIPANTS: Patients discharged from the medical service with diabetes mellitus, congestive heart failure, and/or chronic obstructive pulmonary disease (COPD). MAIN OUTCOME MEASUREMENT: Non-elective readmission within 90 days. RESULTS: Of 1378 patients discharged, 23.3% were readmitted. After controlling for hospital and intervention status, risk of readmission was increased if the patient had more hospitalizations and emergency room visits in the prior 6 months, higher blood urea nitrogen, lower mental health function, a diagnosis of COPD, and increased satisfaction with access to emergency care assessed on the index hospitalization. CONCLUSIONS: Both clinical and patient-centered factors identifiable at discharge are related to non-elective readmission. These factors identify high-risk patients and provide guidance for future interventions. The relationship of patient satisfaction measures to readmission deserves further study.

Case reports of nocardiosis in patients with human immunodeficiency virus (HIV) infection.

INTRODUCTION: We present 4 local cases of nocardiosis in HIV-infected patients and discuss the diagnosis, clinical syndromes and therapy of nocardiosis. CLINICAL PICTURE: Two cases presented with pulmonary nocardiosis, one had a cervical lymph node abscess and one had disseminated nocardiosis with pulmonary, cerebral and soft tissue involvement. TREATMENT: Combination therapy is often employed. Sulphonamides or co-trimoxazole, amikacin, imipenen, minocycline and ceftriaxone are some of the drugs that could be used. OUTCOME: Outcome hinges on the early recognition and optimal treatment of this infection. CONCLUSIONS: Clinical presentations vary and diagnosis is difficult and frequently delayed. Nocardiosis should be suspected in patients who present with pulmonary lesions with soft tissue and/or cerebral abscesses.

In vivo association of pp60v-src and the gap-junction protein connexin 43 in v-src-transformed fibroblasts.

v-src-transformed fibroblasts have significantly reduced levels of gap junction-mediated intercellular communication. This observed downregulation of cellular communication has been associated with tyrosine phosphorylation of the gap-junction protein connexin 43 (Cx43). Previously, we demonstrated that purified, kinase-active pp60src phosphorylates Cx43 in vitro (J Biol Chem 1995; 270:12751-12761). More recently, we reported that this association is mediated by the SH2 and SH3 domains of pp60v-src (J Biol Chem 1997;272:22824-22831). In this report, we present in vivo evidence supporting the hypothesis that Cx43 is an endogenous substrate of pp60v-src in v-src-transformed fibroblasts. Cytological localization studies with confocal microscopy demonstrated that pp60v-src and Cx43 were partially co-localized in regions of the plasma membrane. Cx43 and pp60v-src co-immunoprecipitated from v-src-transformed fibroblasts, indicating that the two proteins were associated, and form a stable complex. Furthermore, pp60v-src could phosphorylate co-immunoprecipitated Cx43 in an immune-complex kinase assay. Two-dimensional phosphopeptide mapping of the immune-complexed Cx43 phosphorylated in vitro demonstrated that the sites of tyrosine phosphorylation were consistent with previously identified sites of pp60v-src phosphorylation. These results provide additional in vivo evidence that Cx43 is a direct substrate of pp60v-src in v-src-transformed fibroblasts. The ability of pp60v-src to alter gap junction-mediated cellular communication may serve as one mechanism by which pp60v-src initiates and/or maintains aspects of cellular transformation.

Phylogenetic relationships of Salmonella typhi and Salmonella typhimurium based on 16S rRNA sequence analysis.

The 16S rRNA gene sequences of Salmonella typhi and Salmonella typhimurium were amplified by PCR, cloned, and sequenced. These sequences were analyzed by comparison with reference organisms from the family Enterobacteriaceae. Both S. typhi and S. typhimurium belong to the gamma subdivision of the class Proteobacteria.

Tyrosine phosphorylation of connexin 43 by v-Src is mediated by SH2 and SH3 domain interactions.

Reduction of gap junctional communication in v-src transformed cells is accompanied by tyrosine phosphorylation of the gap junction protein, connexin 43 (Cx43). Cx43 is phosphorylated on tyrosine by v-Src. The Src homology 3 (SH3) and Src homology 2 (SH2) domains of v-Src mediate interactions with substrate proteins. SH3 domains interact with proline-rich peptide motifs. SH2 domains associate with short amino acid sequences containing phosphotyrosine. We present evidence that the SH3 and SH2 domains of v-Src bind to proline-rich motifs and a phosphorylated tyrosine residue in the C-terminal tail of Cx43. Cx43 bound to the SH3 domain of v-Src, but not c-Src, in vitro. Tyrosine-phosphorylated Cx43 bound to the SH2 domain of v-Src in vitro. v-Src coprecipitated with Cx43 from v-src-transformed Rat-1 fibroblasts. Mutations in the SH3 and SH2 domains of v-Src, and in the proline-rich region or tyrosine 265 of Cx43, reduced interactions between v-Src and Cx43 in vivo. Tyrosine phosphorylation of Cx43 was dependent on the association of v-Src and Cx43. These results provide further evidence for the direct involvement of v-Src in tyrosine phosphorylation of Cx43 and inhibition of gap junctional communication in v-src-transformed cells.